The alkaloid epibatidine, i.e. 2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane, was first isolated in 1974 from the skin of the Ecuadorian frog Epipedobates tricolor. Shortly afterwards, its analgesic potency was shown to be about 200-fold higher than that of morphine. Regrettably however, the toxicity of epibatidine is too high for any human therapeutic use. The mode of action of epibatidine was later revealed as a highly potent nicotinic acetylcholine receptor agonist. The membrane bound pentameric ion channel has been associated with many neurological disorders such as Alzheimer's disease, Parkinson disease and schizophrenia. For each of these disorders, there is a shift in the prevalence of the different nicotinic acetylcholine receptor subtypes.
In order to improve the ratio of pharmacological to toxicological activity, many analogues have been synthesized. Most of them are substituted at position 2 of the 7-azabicyclo-[2.2.1]heptyl ring, e.g. WO 00/23424, U.S. Pat. Nos. 6,060,473, 5,817,679, 6,117,889, 6,077,846, 5,510,490, EP 657,455, U.S. Pat. No. 6,562,816, and EP 955,301. Grygorenko et al in Tetrahedron (2006) 17:252 has also disclosed one derivative substituted at position 1 of the 7-azabicyclo-[2.2.1]heptyl ring, i.e. 7-(1-phenylethyl)-7-azabicyclo-[2.2.1]heptyl-1-carbonitrile.
As disclosed by Collingridge et al in Neuropharmacology (2009) 56:2-5 (especially table 1) and in accordance with the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification, nicotinic acetylcholine receptors (hereinafter nAChR) belong to the Cys-loop superfamily of receptors (also including GABA, 5-HT3, glycine and zinc activated receptors) which itself is part of ligand-gated ion channels activated by neurotransmitters (also named the neurotransmitter-gated ion channel superfamily).
nAChR are widely distributed throughout the central (CNS) and peripheral (PNS) nervous systems. Such receptors play an important role in regulating CNS function, particularly by modulating release of a wide range of neurotransmitters such as acetylcholine, norepinephrine, dopamine, serotonin and GABA, and are consequently involved in a wide variety of complex brain functions such as neurodegeneration, pain and inflammation, psychosis, mood and emotion, memory, attention and cognition as well as in pathological conditions such as Alzheimer's and Parkinson's disease, schizophrenia, epilepsy, pain and nicotine addiction. At least 16 different genes code for nAChR subunits, which can assemble as pentamers in different combinations to form diverse nAChR subtypes. nAChR are ligand-gated ion channels formed by the assembly of five subunits (pentamers). Each subunit is comprised of a large extracellular N-terminal. The agonist binding site is located in the N-terminal, at the interface between two adjacent subunits. 17 distinct nAChR subunits have been identified. Besides the muscular nAChR subtypes, the neuronal nAChR can be divided in two groups:                α-bungarotoxin sensitive receptors which can be homomeric (being composed of five α7 or α9 subunits) or heteromeric (made up of different α7 or α9 or α10 subunits); and        α-bungarotoxin insensitive receptors which consist of different heteromeric combinations of α(α2-α6) and β (β2-β4) subunits, whose prevalent stoichiometry is believed to be (α)2(β)3.        
The α7 subtype and the predominant α4β2 subtypes of nAChR have been recognized as being of major importance since they play a significant role in enhancing cognitive function, protection against neuron degeneration, schizophrenia and pain relief. The activity of both α7 and α4β2 nAChR can be modified or regulated by means of subtype-selective nAChR ligands which can exhibit antagonist, agonist or partial agonist properties. The number of binding sites depends on the number and type of α subunits: for instance in (α7)5, five identical binding sites are present, whereas in (α4)2(β2)3 there are two binding sites located at the interface between the α4 and β2 subunits.
α7 subunits uniquely and efficiently assemble into functional homopentameric acetylcholine-gated non selective cation channels when expressed in mammalian cells. The α4β2 and α3β4 subtypes are also well characterized in terms of ligand selectivity. A few other subtypes such as α2β4, α4β4, α3β2, and α1β1γδ, have also been evaluated for instance by Broad et al in J. Pharmacol. Exper. Therap. (2006) 318:1108-1117. There is currently significant interest in developing selective nAChR agonists and modulators, in particular selective ligands for the α7, α4β2, α3β4 α2β4, α4β4, α3β2, and α1β1γδ subtypes of nAChR, for the treatment of various neurological, neurodegenerative and psychiatric disorders.
More particular, there is still a need in the art for more subtype selective nAChR modulators such as epibatidine analogues in an effort to provide prevention or treatment for neurological, neurodegenerative and psychiatric diseases such as, but not limited to, Alzheimer disease, Parkinson disease, epilepsy, pain, nicotine addiction, mood instability, dementia and schizophrenia, as well as other CNS disorders such as impaired memory performance, impaired attention and cognitive deficit. The present invention intends to address one or more of these problems.